The proposed research will develop new methodologies utilizing mass spectrometry for examining protein structure, which is the key to understanding protein function and critical for a molecular level understanding of virtually every disease. This research will enable facile new experiments for studying protein folding and verifying native protein folds, etc... Particular emphasis will be placed on examination of natively unfolded proteins, a reclusive class of molecules related to many neurological diseases and cancer. These goals will be achieved by experiments utilizing noncovalent mass tags designed to respond to the chemical availability of select amino acid side chains on protein surfaces. By facilitating access to protein structure via simple yet sensitive experiments which can be carried out in less than a day, human health will be benefited in diverse ways. More specifically, this technique will be used to study the mechanism by which alpha-synuclein improper aggregates which is implicated in diseases such as Parkinson's and Alzheimer's.